Overview: Aspergillus fumigatus
is a highly prevalent airborne fungus that
causes the disease aspergillosis (Figure
1). It is a filamentous
saprophytic
fungus that grows in multicellular filaments
called hyphae by feeding on dead or decaying
organic matter. A. fumigatus is most
commonly found in soil, feeding on waste
substrates to obtain nutrients and energy via
biodegradation. Biodegradation
naturally helps the ecosystem recycle dead
organisms or waste as a means to help continue
the cycle of life and replenish the soil and
environment with carbon and nitrogen. Typically,
A. fumigatus secrete hydrolytic enzymes
from hyphal tips that help cleave starches,
hemicelluloses, cellulose, and other sugar
polymers the body cannot digest. This organism
is also thermotolerant; it has the ability to
thrive at greater than 37°C, thereby increasing
its germination efficiency and growth rate.

Figure 1.
This photomicrograph depicts the appearance of a
conidiophore (stalk) of the fungus
Aspergillus fumigatus.

Although A. fumigatus
fungi primarily feed on decaying
vegetation, they can also dine on substrates as
diverse as dung, human tissues, and antique
parchment. Moulds
produced by this pathogen are capable of
degrading manmade substrates such as textiles
and paper in a process known as
biodeterioration. Nuts, spices, and grains
that are low in water are the most attractive
foods to be spoiled by A. fumigatus.
A. fumigates morphology varies
depending on the amount of oxygen and the
temperature and humidity available.

Characteristically, this
species can reproduce asexually by producing
airborne spores (conidia)
and sexually as well. They are also able to
thrive in harsh conditions and in extreme
temperatures, and thus are categorized as
opportunistic pathogens. A. fumigatus
fungi are commonly isolated from soil, plant
debris, indoor air environments and other such
oxygenated areas, where they are constantly
undergoing aerobic decomposition (Figure
2). Environmental surveys indicate that in
areas of human habitation, approximately 1 to100
A. fumigatus conidia are typically
found per cubic metre of air, and thus all
humans inhale at least several hundred conidia
per day. Hence, they are part of the normal
flora in humans, where they exist in the mucous
membranes of the upper respiratory tract. These
conidia, however, are beneficial in that they
compete with other, potentially more dangerous
microorganisms that can essentially harm the
host. Infections arise when conidia enter the
lungs, germinate on lung alveoli, and produce
mycelium which penetrates lung tissue.

Clinical Infections:
As mentioned earlier, aspergillosis
is the prominent illness caused by A.
fumigatus. There are many different kinds
of aspergillosis. One kind is allergic
bronchopulmonary aspergillosis, a condition
where the fungus causes allergic respiratory
symptoms, such as wheezing and coughing, but
does not actually invade and destroy tissue.
Another kind of aspergillosis is invasive
aspergillosis, a disease that usually affects
people with immune system problems. In this
condition, the fungus invades and damages
tissues in the body. Invasive aspergillosis most
commonly affects the lungs, but can also cause
infection in many other organs and can spread
throughout the body.

Aspergillus infections of the
nose and paranasal sinuses are also quite
common, especially in individuals who are
immunocompromised (people with AIDS or cancer).
High fever, chest pain, cough, and
breathlessness are preliminary symptoms of
paranasal sinus infections. Moreover, due to the
proximity of sinuses near the brain, often
anaerobic bacteria can carry the pathogen to the
brain, resulting in more serious conditions such
as cerebral (or brain)
abscess.
Inflammation is caused by a burst of cytokines
which increase blood flow to the targeted region
and stimulate a defense response by activating
lymphocytes.

Virulence: A.
fumigatus produces a variety of secondary
metabolites, including the mycotoxin,
gliotoxin. When conditions are right,
A. fumigatus fungi proliferate into
colonies (moulds) and mycotoxin levels become
high. More specifically, the gliotoxin
biosynthetic pathway is catalyzed by a
nonribosomal peptide synthase encoded by the
gliP gene. These mycotoxins are neither
necessary for growth nor the development of the
fungi, but effectively weaken the immune system
of the invaded host. Furthermore, the mycotoxin,
gliotoxin, possesses immunosuppressive
properties, causing apoptosis in certain types
of mammalian cells of the immune system,
including neutrophils, eosinophils,
granulocytes, macrophages, and thymocytes.
A. fumigatus is the most prolific producer
of gliotoxin among all other pathogenic
Aspergillus species.

The metabolite gliotoxin also
acts as an inhibitor of the enzyme farnesyl
transferase and NADPH oxidase activity
responsible for the neutrophil oxidative burst.
It noncompetitively inhibits the
chymotrypsin-like activity of the 20S proteasome,
and displays anti-inflammatory activity. In
fact, even nanomolar concentrations of gliotoxin
can inhibit the activation of transcription
factor NF-κB (κ = kappa) (nuclear factor
kappa-light-chain-enhancer of activated B cells)
in response to a variety of T cell and B cell
stimuli. NF-κB is normally held in the cytoplasm
in an inactivate state by IκB (inhibitory
protein). The goal is to release the attached
transcription factor so it can translocate to
the nucleus and turn on transcription of mRNA.
Moreover, the mycotoxin has been shown to affect
heart and other tissues, and cause neurosis or
premature death of cells. Levels of gliotoxin
can be tested by urine and blood samples.

Treatment:
The favoured treatment with the fewest side
effects, such as nephrotoxicity, is voriconazole.
Other drugs used such as amphotericin B,
caspofungin, flucytosine, itraconazole are used
to treat this fungal infection. For severe cases
of invasive aspergillosis a combination therapy
of voriconazole and caspofungin is suggested as
a first line treatment. However, the best thing
that one can do to avoid aspergillosis or
decrease the risk is to avoid dusty areas, such
as construction sites the pathogen tendd to
accumulate.